The present invention relates to a pharmaceutical formulation with delayed active ingredient release that contains 1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol or one of its pharmaceutically acceptable salts in a matrix.
1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol is known from U.S. Pat. No. 6,248,737 (=EP 693,475), the entire disclosure of which is incorporated by reference, as an analgesically active medicament and may be administered orally. The usual formulations for oral administration of 1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol lead to a rapid release of the active ingredient in the gastrointestinal tract, resulting in a rapid onset of the analgesic effect. At the same time it is observed that the effect rapidly wears off. Accordingly the treatment of severe chronic pain using 1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol has hitherto required the medicament to be administered at relatively short intervals, for example 4 to 6 times a day, in order thereby to ensure a sufficient concentration of active ingredient in the patient's blood plasma. The necessity of a frequent dosage easily leads however to mistakes in administration of the medicament as well as to undesired plasma concentration fluctuations, which has a deleterious effect as regards patient compliance and therapeutic usefulness, especially in the treatment of chronic pain conditions. A pharmaceutical application form with delayed release (retard formulation) for oral administration of the active ingredient 1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol is therefore desirable.
In the prior art, retard formulations are generally known for a large number of various active ingredients. Conventional retard forms include, inter alia, coated retard forms and matrix retard forms.
In coated retard forms such as those described, for example, in U.S. Pat. No. 4,728,513 (=DE 36 25 458), the core of a pharmaceutical composition containing an active ingredient is provided with a coating of one or more hydrophilic and/or hydrophobic polymers that delays the release of the active ingredient.
In matrix retard forms, the active ingredient is contained in a matrix formed from one or more carrier materials, which controls the release of the active ingredient. Thus for example, U.S. Pat. No. 4,389,393 (=DE 33 09 516) discloses a process for the production of matrix formulations with hydroxypropylmethyl-cellulose (HPMC) as carrier material and to some extent a delayed release of the active ingredient, wherein the active material does not comprise more than one third of the weight of the formulation and consists of at least one hydroxypropylmethylcellulose that has a methoxy content of 16-24 wt. %, an hydroxypropyl content of 4-32 wt. % and a number average molecular weight of at least 50,000. The formulations disclosed in U.S. Pat. No. 4,389,393 contain HPMCs with viscosities (in 2 wt. % aqueous solution at 20° C.) between 15 and 30,000 cPs (15 to 30,000 mPa·s). A release behavior independent of the pH value of the dissolution medium is not disclosed in U.S. Pat. No. 4,389,393.